DE3722540C2 - - Google Patents

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Publication number
DE3722540C2
DE3722540C2 DE3722540A DE3722540A DE3722540C2 DE 3722540 C2 DE3722540 C2 DE 3722540C2 DE 3722540 A DE3722540 A DE 3722540A DE 3722540 A DE3722540 A DE 3722540A DE 3722540 C2 DE3722540 C2 DE 3722540C2
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Prior art keywords
fish oil
emulsion
weight
solvent
fat emulsion
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DE3722540A1 (en
Inventor
Klaus Dr. Sommermeyer
Burghard Dr.Med. Priv.-Doz. 6365 Rosbach De Weidler
Angelos N. Prof. Dr. Sagredos
Konrad 2000 Hamburg De Remse
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Fresenius SE and Co KGaA
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Fresenius SE and Co KGaA
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56Materials from animals other than mammals
    • A61K35/60Fish, e.g. seahorses; Fish eggs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/20Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids

Description

Fat emulsions for parenteral purposes serve the supply of patients with essential or complementary Nutrients that bypass the patient normal digestive route by intravenous Infusions are supplied.

Fat emulsions for infusion purposes are already known. From the PCT application Publication no. WO 87/02 247 is a fat emulsion for parenteral use known, the concentrations of 5 to 50 wt .-% of highly purified fish oils, the concentration of the free fatty acids in the emulsion below 5 mEq / l lies. Furthermore, the fish oil used is a relatively high compared to the free fatty acids Have concentration of fatty acid esters. On which How the highly purified fish oils are made and what other quality criteria, such as salary dimeric, oligomeric and oxidized triglycerides as well of cholesterol that fish oils meet is this Font not to be found.

In DE-OS 34 09 793 is a liquid emulsion described a fatty acid having 20 to 22 carbon atoms or their esters or a mixture of two or more such fatty acids or esters, further a vegetable oil, an emulsifier and water. The fatty acids or their esters may be in the form of a purified fish oil. Although will be on it noted that the fish oils used for the emulsion be cleaned beforehand to adverse reactions  to avoid in the living body. From the example 3, in particular Table 1, this publication, the only one under the production of an emulsion Describes how to use a fish oil, but it does that referred to as purified sardine oil a Content of over 46% of free fatty acids and over 10% unsaponifiables (hydrocarbons and sterols) having. Accordingly, such a "purified" fish oil contains still a high percentage of ingredients that are no essential or supplemental nutrients and those undesirable upon parenteral administration Side reactions can cause and therefore the patient unnecessarily burdened when fed to it.

In contrast to the fatty and oily substances used to Production of foodstuffs, especially of edible fat products, must be used on the glyceride oils, for the preparation of fat emulsions for infusion purposes to be used in human medicine, for safety reasons to avoid health Damage to the patient particularly high demands with regard to the purity of the individual components and the constant quality of the overall composition become. PCT application WO 87/02 247 and the However, DE-OS 34 09 793 are no references or suggestions to see how highly purified such fish oils need to be in order for them to be healthier of the patient harmless in the form of fat emulsions can be used in infusions.

Recent analytical studies have shown that the conventionally fully refined glyceride oils still noticeable amounts of accompanying substances, in particular on dimeric, oligomeric and oxidized triglycerides as well  of cholesterol. These unwanted accompanying substances especially in the refining of such Glyceride oils which, such. As the fish oils, larger Proportions of polyunsaturated fatty acids in the triglyceride dressing contain and therefore particularly sensitive towards oxidation and addition reactions. The discovered amounts of impurities cause usually when using these oils in foods no noticeable deterioration of taste, Odor and storage properties in the final products. For higher quality standards, as they are for use such glyceride oils for dietary and parenteral Purposes, in particular for infusions However, it is desirable to add glyceride oils Use as free as possible from such unwanted Accompanying substances.

The present invention is therefore based on the object improved fat emulsions using Glyceride oils containing eicosapentaenoic acid and / or docosahexaenoic acid in the triglyceride dressing create a consistent with great reliability possess high quality standard and essentially free of the above-mentioned undesirable accompanying substances are so that these fat emulsions harmless be used for dietary and parenteral purposes can.

This object is achieved by a parenterally administrable fat emulsion with a content of distilled water, emulsifier, emulsion stabilizer or Isotonisierungszusatz and 5 to 50 wt .-% of a glyceride, the highly refined, enriched in ω -3 fatty acids in the triglyceride dressing fish oil with a content from 25 to 50% by weight of eicosapentaenoic acid and docosahexaenoic acid in the triglyceride dressing, obtainable by the following process steps, starting from a degummed, deacidified and bleached fish oil containing ω- 3-fatty acids in the triglyceride dressing:

  • a) mixing the fish oil with one with the fish oil miscible, volatile solvent in the weight / volume ratio Fish oil to solvent from 1: 1 to 1: 5 and Cool the mixture to a temperature in the range from -15 to -80 ° C;
  • b) filtering off the cooled mixture from the insoluble, wherein the filtrate gently freed from the solvent and the fish oil so treated for 2 to 4 hours 180 to 220 ° C is attenuated;
  • c) picking up the steamed fish oil in a non-polar Solvent and filtering the resulting solution via a nonpolar solvent silica gel;
  • d) then gentle removal of the nonpolar solvent and heating of the resulting highly refined and enriched in ω -3 fatty acids fish oil under nitrogen atmosphere at 50 to 60 ° C, filtering through a membrane filter and adding portions with stirring to a likewise heated to 50 to 60 ° C. aqueous mixture containing emulsifier, emulsion stabilizer or isotonization additive and Coemulgator;
  • e) further emulsifying the crude emulsion formed at 60 to 70 ° C and then filtered under a nitrogen atmosphere through a membrane filter; and  
  • f) one or more stages of homogenization of the emulsion at 70 to 85 ° C, whereupon the resulting fat emulsion under nitrogen to a temperature in the range of Cooled to 5 to 10 ° C, optionally to a pH Value adjusted from 8.5 to 8.8 and in appropriate Is bottled under exclusion of oxygen,

wherein the fish oil in the resulting fat emulsion at least 95% by weight of monomeric triglycerides, less than 2 Wt% oxidized triglycerides, less than 0.2 wt% trimeric and oligomeric triglycerides, less than 0.8 Wt% dimeric triglycerides and less than 1.5 wt% Unsaponifiable as well as less than 2500ppm cholesterol having.

As is known, fish oils contain eicosapentaenoic acid and docosahexaenoic acid in the triglyceride dressing, which are vital components as ω -3 highly unsaturated fatty acids, which have to be supplied to the body and which have important biological significance, for example as a precursor of the prostaglandins and as structural elements of the membrane lipids. Furthermore, one attributes to these acids an antithrombotic and lipid-lowering effect. Since their isolation from natural products and their chemical synthesis are very costly, fish oils are a relatively cheap source of these essential fatty acids. Their use in fat emulsions useful for parenteral purposes requires, however, that the fish oils are of a highly purified quality so that parenteral use can safely prevent health harm or intolerance to the patients. For the reasons mentioned above, it is further desired that the highly refined fish oils are enriched with omega- 3 fatty acid triglycerides. All of these requirements are met to a high degree by the present invention, which makes it possible to provide high quality fat emulsions for parenteral use.

The fat emulsion according to the invention is characterized by a content of highly refined fish oil, which is enriched by means of a specific method, which will be discussed in more detail, to ω -3 fatty acids in the triglyceride dressing. This fish oil contains at least 95% by weight, preferably at least 98% by weight of monomeric triglycerides, less than 2% by weight, preferably less than 1% by weight of oxidized triglycerides, less than 0.2% by weight, preferably less than 0.1% by weight of trimeric and oligomeric triglycerides, furthermore less than 0.8% by weight, preferably less than 0.5% by weight of dimeric triglycerides and less than 1.5% by weight, preferably less as 0.8 wt .-% unsaponifiable, including in particular hydrocarbons and sterols are expected. The total content of fish oil in eicosapentaenoic acid and docosahexaenoic acid in the triglyceride dressing is in the range from 25 to 50% by weight, preferably in the range from 35 to 50% by weight, in each case determined as area percentages in the gas chromatogram.

While fish oils usually have a cholesterol content of have about 4000 to 12 000 ppm, the content is Cholesterol in the fish oils of the fat emulsion according to the invention less than 2500 ppm, preferably less than 1500 ppm.

The enriched in the fish oil l -3-Fettsäuretriglyceride contain as fatty acid component predominantly eicosapentaenoic acid and docosahexaenoic acid. These can be present in different proportions to each other, which can be determined by measuring the associated areas in the gas chromatogram (GC). These proportions are dependent on the nature of the fish oil used and the degree of accumulation achieved at ω -3 fatty acids. It has been found that fish oils in which eicosapentaenoic acid and docosahexaenoic acid are present in the triglyceride dressing in a proportion corresponding to a GC area ratio of eicosapentaenoic acid to docosahexaenoic acid in the range of 0.5 to 2.6 provide excellent quality fat emulsions, therefore, ratios in This area is particularly preferred.

The essential component of the fat emulsion according to the invention is naturally a highly refined, enriched with ω -3 fatty acids fish oil, which can be obtained for example from a Pilchard oil, Menhadenöl, Perufischöl, sardine oil, salmon oil, herring oil and / or mackerel. To prepare the emulsions, emulsifiers which are physiologically compatible, for example purified lecithins, such as. As soy lecithin, egg lecithin or fractions thereof, can be used. In addition, the fat emulsion according to the invention expediently contains an additive for stabilizing and isotonizing the fat emulsion, such. As glycerol, and small amounts of a co-emulsifier, which acts as an emulsifying aid, such as. As alkali salts of fatty acids. The fat emulsions according to the invention are always oil-in-water (O / W) emulsions in which the outer, continuous phase consists of distilled water suitable for parenteral use.

The constituents mentioned can be present in very different proportions in the fat emulsion according to the invention. A preferred embodiment of the fat emulsion according to the invention contains from 5 to 45% by weight highly refined fish oil enriched in ω- 3 fatty acids, 1 to 2% by weight emulsifier, 1 to 3% by weight emulsion stabilizer or isotonization additive, 0.02 to 0.05 wt .-% Coemulgator and the remainder water. Particularly preferred is a fat emulsion with 8 to 35 wt .-% hochraffiniertem enriched in l -3 fatty acids fish oil, 1 to 1.5 wt .-% emulsifier, 1.5 to 2.5 wt .-% emulsion stabilizer or isotonization additive , 0.03 wt .-% Coemulgator and the balance water.

The invention further relates to a process for the preparation of the fat emulsion according to the invention using a degummed, deacidified and bleached fish oil containing ω -3 fatty acids in the triglyceride association, which is characterized in that the fish oil with a miscible with the fish oil, volatile solvent in Weight / volume ratio of fish oil: Solvent from 1: 1 to 1: 5 mixed and the mixture is cooled to a temperature in the range of -15 to -80 ° C, then filtered from the insoluble, the filtrate gently freed from the solvent and the fish oil thus treated is steamed for 2 to 4 hours at 180 to 220 ° C, the steamed fish oil is taken up in a non-polar solvent and the solution is filtered through a eingegelmmte with nonpolar solvent silica gel column, then after gentle removal of the nonpolar solvent, the highly refined and obtained ω -3 fatty acids enriched fish heated under nitrogen atmosphere to 50 to 60 ° C, filtered through a membrane filter and then added in portions to an equally heated to 50 to 60 ° C aqueous mixture containing emulsifier, emulsion stabilizer or Isotonisierungszusatz and Coemulgator, added with stirring, the crude emulsion formed further emulsified at 60 to 70 ° C and then filtered under nitrogen pressure through a membrane filter and finally a single or multi-stage homogenization at 70 to 85 ° C is subjected, whereupon the resulting fat emulsion under nitrogen to a temperature in the range of 5 to 10 ° C. cooled, optionally adjusted to a pH of 8.5 to 8.8 and bottled in a suitable manner with exclusion of oxygen.

The raw materials suitable for the process according to the invention Fish oils are first degummed in a conventional manner, deacidified and treated with bleaching earth, the conditions for the individual process steps known in the art and varies according to the composition of the fish oil can be. Subsequently, the fish oil with a mixed with the fish oil miscible, volatile solvent, wherein the weight / volume ratio of fish oil to solvent generally in the range of 1: 1 to 1: 5, preferably ranging from 1: 2 to 1: 3. As with the fish oil miscible, volatile solvent, acetone has proven itself why it is preferably used in the process. The  Mixture is heated to a temperature in the range of -15 to -80 ° C, preferably from -35 to -60 ° C, cooled, wherein the Separate higher melting ingredients. After that is from the Undissolved filtered off, the filtrate gently from the solvent freed and the resulting fish oil 2 to 4 hours at 180 bis 220 ° C, preferably 2½ to 3 hours at 180 to 200 ° C, attenuated. Because of the high content of unsaturated fatty acids in the triglyceride dressing of fish oil, the thermal load must be kept as low as possible during damping, d. H. the usual damping temperatures, at about 200 to 240 ° C, and the usual damping time, at 5 to 7 Hours, must be significantly reduced if possible become.

The steamed fish oil is in a non-polar solvent absorbed, for example in pentane, hexane, cyclohexane, heptane, Petroleum benzine or a mixture of these solvents. The solution is over a likewise with nonpolar solvent slurried silica gel column, wherein for the Silica gel column is an activated silica gel with a particle size of about 0.05 to 0.2 mm is used. The weight ratio Silica gel to fish oil can be varied within wide limits for economic reasons and because of the lighter ones Handling is the acidification of fish oil over silica gel preferably with a weight ratio of silica gel to fish oil of 1: 1 performed.

Also, the concentration of fish oil in the nonpolar solvent can vary widely, taking for the Columning a solution of 5 to 75 wt .-% fish oil in one nonpolar solvent is preferably used.

The non-polar solvent is then gently removed and heats the highly refined and enriched in ω-3 fatty acids of fish oil obtained under nitrogen atmosphere to 50 to 60 ° C from the resulting eluate. The heated fish oil is passed through a membrane filter, e.g. B. a nylon membrane filter with a pore size of 0.2 microns, filtered and then added in portions to a likewise heated to 50 to 60 ° C aqueous mixture containing emulsifier, emulsion stabilizer and Coemulgator, added with stirring. This forms a crude emulsion, which is further emulsified at 60 to 70 ° C and then under nitrogen pressure through a membrane filter, for. B. such with a pore diameter of about 40 microns, is filtered.

The subsequent homogenization can be one or more stages be carried out, for example, 4-stage and preferably in 3 steps. Here, the temperatures at 70 to 85 ° C. held. In a particularly preferred 3-stage homogenization the temperature is conducted so that the emulsion after the first Homogenisierstufe a temperature of 70 ° C, after the second Homogenierstufe of 80 ° C and after the third Homogenisierstufe of 80 to 85 ° C.

The fat emulsion obtained after homogenization is subjected to Nitrogen to a temperature in the range of 5 to 10 ° C. cooled, optionally to a pH of 8.5 to 8.8 set, z. B. in that a corresponding amount of 1n Sodium hydroxide solution is added, and then suitably bottled under exclusion of oxygen, for example for parenteral Purposes in glass containers, wherein the fat emulsion before the filling again through a membrane filter, for. B. one those with a pore diameter of 2 to 8 microns, filtered can be.  

The fat emulsions according to the invention are outstandingly suitable both for the preparation of dietetic preparations and for parenteral purposes, in particular for infusions. The production process according to the invention makes it possible to process highly refined fish oils enriched in the triglyceride dressing with omega- 3 fatty acids, in particular only eicosapentaenoic acid and fatty acid emulsions of exceptionally constant quality, so that the fat emulsions according to the invention are standardized without difficulty can. This in turn means a virtually risk-free and safe handling of these fat emulsions in parenteral applications.

The invention will be further understood by reference to the following examples explained.

Example 1 Production of highly refined and enriched with polyunsaturated ω -3 fatty acids fish oil

The starting product was a crude fish oil used, the had the following fatty acid composition:

fatty acids GC area% C 12: 0 0.1 C 14: 0 7.7 C 15: 0 0.7 C 16: 0 18.7 C 16: 1 6.8 C 16: 2 0.7 C 17: 0 0.4 C 18: 0 3.4 C 18: 1 10.6 C 18: 2 1.4 C 18: 3 0.7 C 18: 4 2.8 C 20: 0 0.3 C 20: 1 1.0 C 20: 2 0.3 C 20: 3 0.1 C 20: 4 1.7 C 20: 5 13.8 C 22: 0 0.1 C 22: 1 0.3 C 22: 5 2.3 C 22: 6 17.8 C 24: 0 0.1 C 24: 1 0.8

The raw fish oil was first a conventional degumming, subjected to alkaline deacidification and bleaching, such as described below:

a) degumming

100 kg of crude fish oil were heated under nitrogen to 70 ° C, added with stirring 1 kg of a 50% citric acid solution and stirred at 70 ° C for 10 minutes. It was then cooled to 25 ° C. with stirring. Then, 1.5 kg of water was added and stirred at room temperature for 60 minutes. Thereafter, the mixture was at 4400 rpm for 20 minutes. centrifuged and the bare oil decanted from the sediment.
Yield: 97.5 kg; Acid number: 4.6.

b) Alkaline deacidification

97.5 kg of degummed fish oil were heated to 80 ° C. While stirring rapidly, 2.75 l of a 4N sodium hydroxide solution were added to. Thereafter, the stirring was stopped and 10 l 95 ° C hot water aufgeraust. The soap phase was drained and the oil phase twice with 10 l of 0.1N sodium hydroxide solution rewashed. Subsequently, twice with each 20 l  saturated saline, then once with 20 liters of water washed neutral. After drying the oil at 90 ° C / l hPa 95 kg of oil were obtained.

c) bleaching

95 kg of the deacidified oil was mixed with 1.425 kg (1.5%, based on oil) bleaching earth and 20 minutes at Stirred at 90 ° C / l hPa. After filtration through a Seitz filter (Seitz-Fimacel 3) were 91.7 kg of oil.

Subsequent to the bleaching, in the next stage of the process, the enrichment of the omega- 3 fatty acid moieties in the fish oil was carried out as follows:

d) concentration of the bleached fish oil with ω -3-fatty acids in Triglyceridverband

90 kg of degummed, deacidified and bleached fish oil were dissolved in 270 l of acetone and the solution within cooled from 4 hours with stirring to -15 ° C and then filtered. The filtrate was within 4 hours further cooled to -35 ° C and filtered again. The filtrate was freed from the acetone by distillation. you received 13.5 kg of fish oil with the following analytical data:

fatty acids GC area% C 14: 0 5.3 C 15: 0 0.5 C 16: 0 9.4 C 16: 1 8.3 C 16: 2 1.2 C 17: 0 0.1 C 18: 0 1.0 C 18: 1 10.4 C 18: 2 1.5 C 18: 3 0.8 C 18: 4 3.6 C 20: 1 1.0 C 20: 2 0.3 C 20: 3 0.2 C 20: 4 2.7 C 20: 5 18.7 C 22: 1 0.1 C 22: 5 3.0 C 22: 6 23.1 C 24: 1 0.5 1.2% unsaponifiables 6.2% oxidized triglycerides 0.85% dimeric triglycerides 0.15% trimeric triglycerides 9026 mg / kg cholesterol

Sensory: The product smelled strongly fishy.

e) attenuation

13.5 kg of fish oil enriched in ω- 3-fatty acids were steamed for 3 hours at 180 ° C / l hPa with 5% steam throughput / h. The steamed fish oil had the following analytical data:

1.2% unsaponifiables 7.9% oxidized triglycerides 1.95% dimeric triglycerides 0.45% trimeric triglycerides 17.8% eicosapentaenoic acid 23.8% docosahexaenoic acid 9217 mg / kg cholesterol

f) high refining over silica gel column

13 kg of the steamed fish oil was dissolved in 26 liters of hexane. The solution was applied by means of a pump on a silica gel column by slurrying 13 kg of silica gel with a particle size in the range of 0.05 to 0.2 mm with 26 l of hexane in a 50 l steel column with a diameter of 12 , 5 cm had been made. The throughput of the solution through the silica gel column was 5 l / h. The eluate obtained was largely freed from the hexane at 60 ° C. and 25 hPa, and the residual solvent was stripped with nitrogen in a water-ring vacuum at 90 ° C. There were obtained 10.7 kg of a highly refined, enriched in ω-3 fatty acids of fish oil with the following analytical data:

fatty acids GC area% C 14: 0 7.2 C 15: 0 0.6 C 16: 0 13.2 C 16: 1 8.5 C 16: 2 1.3 C 17: 0 1.1 C 18: 0 1.6 C 18: 1 19.8 C 18: 2 1.6 C 18: 3 0.8 C 18: 4 4.2 C 20: 1 0.7 C 20: 4 2.3 C 20: 5 18.1 C 22: 5 2.4 C 22: 6 23.3

Acid value | 0.2 unsaponifiables 0.4% oxidized triglycerides <0.1% dimeric triglycerides 0.4% trimeric triglycerides <0.05% cholesterol 1353 mg / kg

Sensory: barely perceptible fishy smell.

The results of this example show that the "winterization" carried out after conventional degumming, deacidification and bleaching in step d) gives a marked accumulation of ω3 -fatty acids, but that there is still a noticeable amount of unsaponifiable, oxidized triglycerides and Cholesterol are present in the thus treated fish oil and the sensor is unsatisfactory. The analytical data of the steamed fish oil show that the levels of unwanted impurities are unchanged high or even increased, and only by the treatment of the steamed fish oil with activated silica in the last stage of the process according to the invention is obtained a practically liberated from the accompanying substances, highly enriched fish oil with eicosapentaenoic acid and docosahexaenoic acid with a barely perceptible fishy odor which is well suited for the fat emulsion according to the invention.

example 2

As a starting material, 10 kg of the same raw fish oil as used in Example 1 and this in the same manner as in Example 1 treated with the difference that the second enrichment step of ω -3 fatty acids instead of -35 ° C at -80 ° C. has been. The fish oil obtained after treatment with activated silica showed the following composition of fatty acids:

fatty acids GC area% C 12: 0 0.1 C 14: 0 2.8 C 16: 0 1.5 C 16: 1 8.8 C 16: 2 1.2 C 17: 0 0.8 C 18: 1 10.0 C 18: 2 1.6 C 18: 3 1.0 C 18: 4 4.5 C 20: 1 1.0 C 20: 2 0.3 C 20: 3 0.2 C 20: 4 3.0 C 20: 5 24.5 C 22: 1 0.3 C 22: 5 3.3 C 22: 6 25.9 C 24: 1 0.2

Treatment of the fish oil in the second enrichment stage at -80 ° C instead of at -35 ° C as in Example 1 results in a shift in the accumulation of polyunsaturated fatty acids in favor of the particularly desirable C 20: 5 and C 22: 6 fatty acids of 18, 1 to 24.5 or 23.3 to 25.9 GC area percentages.

example 3

The starting material was a crude fish oil with the following Composition of fatty acids used:  

fatty acids GC area% C 12: 0 0.2 C 14: 0 7.5 C 16: 0 17.2 C 16: 1 7.9 C 16: 2 0.8 C 17: 0 0.3 C 18: 0 2.3 C 18: 1 12.4 C 18: 2 1.3 C 18: 3 0.9 C 18: 4 3.4 C 20: 0 0.2 C 20: 1 3.4 C 20: 2 0.2 C 20: 4 0.9 C 20: 5 14.7 C 22: 1 4.3 C 22: 5 2.0 C 22: 6 9.6 C 24: 1 0.6

10 kg of this fish oil were, as described in Example 1, first degummed in a conventional manner, deacidified and bleached and then enriched by the inventive method of ω -3 fatty acids and highly refined with the difference that in the second enrichment stage of Gew./Vol Changed the ratio of fish oil to acetone from 1: 3 to 1: 4 and the mixture was now cooled to -50 ° C instead of to -35 ° C. The fish oil obtained after the silica gel gelation had the following analytical data:

fatty acids GC area% C 12: 0 0.1 C 14: 0 3.5 C 16: 0 2.4 C 16: 1 9.1 C 16: 2 1.2 C 18: 0 1.1 C 18: 1 15.1 C 18: 2 2.5 C 18: 3 1.3 C 18: 4 5.8 C 20: 1 2.1 C 20: 2 0.2 C 20: 3 0.2 C 20: 4 2.9 C 20: 5 27.9 C 22: 1 1.4 C 22: 5 2.9 C 22: 6 15.1 C 24: 1 0.2

Yield | 7% unsaponifiables 0.5% oxidized triglycerides <0.1% dimeric triglycerides 0.4% trimeric triglycerides <0.05% cholesterol 1527 mg / kg

The results of this example also show that after the Fish oil treated according to the invention strongly on eicosapentaenoic acid and docosahexaenoic acid enriched in the triglyceride dressing is and practically free of unwanted accompanying substances is and only a relatively low content of cholesterol having.  

example 4

The starting material was a crude fish oil with the following Composition of fatty acids used:

fatty acids GC area% C 12: 0 0.1 C 14: 0 7.9 C 16: 0 18.2 C 16: 1 10.9 C 16: 2 1.4 C 17: 0 0.4 C 18: 0 2.9 C 18: 1 16.4 C 18: 2 0.9 C 18: 3 0.4 C 18: 4 2.4 C 20: 0 0.13 C 20: 1 0.4 C 20: 2 0.1 C 20: 4 0.9 C 20: 5 17.8 C 22: 1 0.1 C 22: 5 1.9 C 22: 6 7.9 C 24: 1 0.3

10 kg of this fish oil were, as described in Example 1, enriched in ω -3 fatty acids and highly refined with the difference that the enrichment stage with a weight / volume ratio of fish oil to acetone of 1: 4 in the first stage at -15 ° C and in the second stage at -60 ° C was performed. The fish oil obtained after columning over a silica gel column showed the following analytical data:

fatty acids GC area% C 14: 0 3.4 C 16: 0 2.3 C 16: 1 11.7 C 16: 2 2.0 C 18: 0 2.6 C 18: 1 12.0 C 18: 2 1.0 C 18: 3 0.5 C 18: 4 4.0 C 20: 1 0.3 C 20: 2 0.1 C 20: 3 0.2 C 20: 4 2.6 C 20: 5 30.5 C 22: 1 0.2 C 22: 5 2.9 C 22: 6 11.9

Yield | 10% unsaponifiables 0.45% oxidized triglycerides <0.1% dimeric triglycerides 0.5% trimeric triglycerides <0.05% cholesterol 1412 mg / kg

This example shows that even for a fish oil which originally had only a moderate content of C 22: 6 fatty acid in the triglyceride group of 7.9 and a rather high content of C 20: 5 fatty acid of 17.8 GC area percent, after the treatment according to the inventive method, an excellent enrichment of these fatty acids to 11.9 and 30.5 GC area percent can be achieved, whereby the amounts of impurities are meaningless and also the cholesterol content is very low.

In the following example it is explained how fat emulsions according to the invention are obtained using fish oils highly refined according to the above Examples 1 to 4 and enriched in ω 3 -fatty acids.

example 5 Preparation of a fat emulsion according to the invention

During the entire preparation the fat emulsion was for it taken care that the components and mixtures are constantly under Nitrogen atmosphere were kept.

First, 12 g of egg lecithin in about 2 minutes under stirring continuously in 75 ml of distilled water for injections, which was heated to 55 to 60 ° C, entered and Then the mixture is stirred for another 15 minutes. Parallel this was done in 25 ml of distilled water for injections, which was also heated to 55 to 60 ° C, 25 g Glycerol (100%) and 0.3 g of sodium oleate were added and slowly dissolved with stirring. The resulting solution was continued maintained at 55 to 60 ° C and with nitrogen pressure within of 10 minutes through a 0.2 μm membrane filter in the prepared Water / lecithin mixture given.

100 g of a highly refined and ω- 3-enriched fish oil obtained in Examples 1 to 4 were heated to 55 to 60 ° C and passed through a nylon membrane filter having a pore size of 0.2 μm within 20 to 25 minutes directly into the prepared aqueous mixture of lecithin, glycerol and sodium oleate with constant stirring, for example, using a high-frequency mechanical device (Ultra-Turrax) for emulsification together with a stirrer given. After completion of the addition of the fish oil, the crude emulsion formed was further emulsified for 25 minutes. During the preparation of the crude emulsion this was maintained at a temperature in the range of 60 to 65 ° C and constantly blanketed with nitrogen.

After switching off the mechanical high-frequency device was the crude emulsion with gentle stirring through a membrane filter with an average pore size of 40 microns under one Nitrogen pressure of about 0.5 bar in one for the production two-stage homogenizer suitable for fat emulsions (1. Stage 400 bar, 2nd stage 100 bar) and homogenized. The temperature was after the first homogenization step about 70 ° C, after the second Homogenisierschritt about 80 ° C. The emulsion was then cooled to 70 ° C and in a storage tank, which is overlaid with nitrogen was. Here the emulsion was allowed to stir occasionally Rest.

Thereafter, the emulsion was still two further Homogenisierschritten subjected to the temperature after the third Homogenizing step about 75 ° C and after the fourth homogenization step at 80 to 85 ° C. Thereafter, the emulsion became so cooled as much as possible and placed in a template that 757 ml cooled to 12 ° C distilled water. Also this process was carried out under a nitrogen atmosphere. With occasional slow stirring, the emulsion was allowed to continue cooled to 8 to 9 ° C. After reaching this temperature the stirrer was switched off.

The pH of the emulsion was tested. Deviations from predetermined setpoint (pH of 8.7 to 8.8) were through Corrected addition of an appropriate amount of 1N sodium hydroxide solution.  The resulting fat emulsion was in a cooling tank under Nitrogen atmosphere stored and before filling by a membrane filter with a pore size of 2 to 8 microns filtered. The filling pressure was a maximum of 0.5 bar. The bottling took place in glass containers, which were subsequently closed were.

The fat emulsions must be protected from light and oxygen to be protected. The bottling is therefore under nitrogen make sure that the oxygen content in the containers as low as possible.

A toxicological test of 10% fat emulsions according to the invention, in a single dose of 38.3 ml / kg Body weight and 46.4 ml / kg body weight intravenously in 6 each male and female Spraque-Dawley rats were injected, revealed within an observation period of 14 days after the application no evidence of toxic Effect. The animals showed a completely undisturbed total abitur and in their behavior no deviations from the Standard. At the section of killed animals after 14 days were not systemic and local pathologic-anatomical Changes observed.

Claims (16)

1. Parenterally administrable fat emulsion with a content of distilled water, emulsifier, emulsion stabilizer or Isotonisierungszusatz and 5 to 50 wt .-% of a glyceride, the highly refined, enriched in ω -3 fatty acids in the triglyceride dressing fish oil with a content of 25 to 50 wt % of eicosapentaenoic acid and docosahexaenoic acid in the triglyceride dressing, obtainable by the following process steps, starting from a degummed, deacidified and bleached fish oil containing ω- 3 fatty acids in the tricylceride dressing:
  • a) mixing the fish oil with a volatile solvent miscible with the fish oil in the weight / volume ratio of fish oil to solvent from 1: 1 to 1: 5 and cooling the mixture to a temperature in the range of -15 to -80 ° C ;
  • b) filtering off the cooled mixture from the insoluble, wherein the filtrate gently freed from the solvent and the thus treated fish oil is steamed for 2 to 4 hours at 180 to 220 ° C;
  • c) picking up the steamed fish oil in a nonpolar solvent and filtering the resulting solution through a silica gel column slurried with nonpolar solvent;
  • d) then gentle removal of the nonpolar solvent and heating of the resulting highly refined and enriched in ω -3 fatty acids fish oil under nitrogen atmosphere at 50 to 60 ° C, filtering through a membrane filter and adding portions with stirring to a likewise heated to 50 to 60 ° C. aqueous mixture containing emulsifier, emulsion stabilizer or isotonization additive and Coemulgator;
  • e) further emulsifying the crude emulsion formed at 60 to 70 ° C and then filtering under a nitrogen atmosphere through a membrane filter; and
  • f) one or more stages of homogenization of the emulsion at 70 to 85 ° C, whereupon the resulting fat emulsion is cooled under nitrogen to a temperature in the range of 5 to 10 ° C, optionally adjusted to a pH of 8.5 to 8.8 and is bottled in a suitable manner with exclusion of oxygen,
wherein the fish oil in the resulting fat emulsion at least 95% by weight of monomeric triglycerides, less than 2 Wt% oxidized triglycerides, less than 0.2 wt% trimeric and oligomeric triglycerides, less than 0.8 Wt% dimeric triglycerides and less than 1.5 wt% Unsaponifiable as well as less than 2500ppm cholesterol having.
2. fat emulsion according to claim 1, characterized the fish oil contains at least 98% by weight of monomeric triglycerides having.
3. fat emulsion according to claim 1, characterized the glyceride oil contains less than 1% by weight of oxidized triglycerides contains.
4. fat emulsion according to claim 1, characterized that the glyceride oil less than 0.1 wt .-% trimer and contains oligomeric triglycerides.
5. fat emulsion according to claim 1, characterized that the glyceride oil less than 0.5 wt .-% dimeric triglycerides contains.
6. fat emulsion according to claim 1, characterized the glyceride oil is less than 0.8% by weight Unsaponifiable contains.  
7. fat emulsion according to any one of claims 1 to 6, characterized characterized in that the glyceride oil is less than 1500 ppm Contains cholesterol.
8. fat emulsion according to any one of claims 1 to 7, characterized characterized in that the glyceride oil has a content of eicosapentaenoic acid and docosahexaenoic acid in the triglyceride dressing from 35 to 50 wt .-%, wherein the weight ratio from eicosapentaenoic acid to docosahexaenoic acid between 0.5 and 2.6 (GC area ratio).
9. fat emulsion according to claims 1 to 8, characterized in that they
5 to 45 wt .-% of highly refined, enriched in ω-3 fatty acids of fish oil,
1 to 2% by weight emulsifier,
1 to 3% by weight of emulsion stabilizer or isotonization additive,
From 0.02 to 0.05% by weight coemulsifier
and the rest contains water.
10. A process for the preparation of a fat emulsion according to claims 1 to 9 using a degummed, deacidified and bleached fish oil containing ω -3 fatty acids in Triglyceridverband, characterized in that the fish oil with a miscible with the fish oil, volatile solvent in the Gew.Vol.-Ververhältnis fish oil to solvent from 1: 1 to 1: 5 mixed and the mixture is cooled to a temperature in the range of -15 to -80 ° C, then filtered from the insoluble, the filtrate gently freed from the solvent and the fish oil thus treated is steamed for 2 to 4 hours at 180 to 220 ° C, the steamed fish oil is taken up in a non-polar solvent and the solution is filtered through a eingegelmmte with nonpolar solvent silica gel column, then after gentle removal of the nonpolar solvent, the highly refined and obtained ω -3 fatty acids enriched fish oil under nitrogen warmed to 50 to 60 ° C, filtered through a membrane filter and then added in portions to an equally heated to 50 to 60 ° C aqueous mixture containing emulsifier, emulsion stabilizer or isotonization and Coemulgator, is added with stirring, the crude emulsion formed at 60 emulsified to 70 ° C and then filtered under nitrogen pressure through a membrane filter and finally a single or multi-stage homogenization at 70 to 85 ° C is subjected, and then cooled the resulting fat emulsion under nitrogen to a temperature in the range of 5 to 10 ° C, optionally adjusted to a pH of 8.5 to 8.8 and filled in a suitable manner with exclusion of oxygen.
11. The method according to claim 10, characterized in that bleached fish oil and solvent, preferably acetone, used in Gew./Vol.- ratio of 1: 2 to 1: 3 become.
12. The method according to claim 10 or 11, characterized that the mixture of bleached fish oil and solvent to a temperature in the range of -35 to -60 ° C is cooled.
13. The method according to any one of claims 10 to 12, characterized characterized in that the attenuation of the fish oil about 2½ is carried out at 180 to 200 ° C for 3 hours.
14. The method according to any one of claims 10 to 13, characterized characterized in that the filtration of the fish oil over Silica gel with a silica gel weight ratio too  Fish oil carried out 1: 1 while using a solution of 5 to 75% by weight of fish oil in a nonpolar solvent is used.
15. The method according to any one of claims 10 to 14, characterized characterized in that the homogenization of the filtered Emulsion is carried out in three stages, preferably such that the temperature of the emulsion after the first Homogenizing at 70 ° C, after the second stage at 80 ° C and after the third stage at 80 to 85 ° C.
DE3722540A 1987-07-08 1987-07-08 Expired - Lifetime DE3722540C2 (en)

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DE88109749A DE3888408D1 (en) 1987-07-08 1988-06-18 Fat emulsion, process for its preparation and its use.
EP88109749A EP0298293B2 (en) 1987-07-08 1988-06-18 Process for the manufacture of fat emulsions and their use
DE1998175015 DE19875015I2 (en) 1987-07-08 1988-06-18 Fat emulsion process for their preparation and their use
AT88109749T AT102834T (en) 1987-07-08 1988-06-18 Fat emulsion, method for their production and their use.
LU90401C LU90401I2 (en) 1987-07-08 1999-05-10 Omegaves
NL990032C NL990032I2 (en) 1987-07-08 1999-10-12 Fat emulsion, process for its preparation and use.

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DE4133694A1 (en) * 1991-10-11 1993-04-15 Fresenius Ag Use of an emulsion for preparing a medicament for i.v. administration for the treatment of skin diseases

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DE3903056A1 (en) * 1989-02-02 1990-08-09 Braun Melsungen Ag Fat emulsion for intraperitoneal application, its production and application
DE3903057A1 (en) * 1989-02-02 1990-08-09 Braun Melsungen Ag Fat emulsion for endotracheal application, its production and application
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DE19503993A1 (en) * 1995-02-08 1996-08-14 Johann Friedrich Dr Med Desaga Enteral product contg n-3-fatty acid or deriv and medium chain length tri:glyceride
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EP0739589B1 (en) * 1995-04-28 2001-06-13 Loders Croklaan B.V. Triglycerides, rich in Polyunsaturated fatty acids
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DE4133694A1 (en) * 1991-10-11 1993-04-15 Fresenius Ag Use of an emulsion for preparing a medicament for i.v. administration for the treatment of skin diseases

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EP0298293B2 (en) 2004-11-24
LU90401A9 (en)
NL990032I2 (en) 2000-04-03
DE3722540A1 (en) 1989-01-19
EP0298293A3 (en) 1990-05-02
NL990032I1 (en) 1999-12-01
DE3888408D1 (en) 1994-04-21
AT102834T (en) 1994-04-15
EP0298293A2 (en) 1989-01-11
LU90401I2 (en) 2000-01-24
DE19875015I2 (en) 2000-03-09
EP0298293B1 (en) 1994-03-16

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